PROJECT SUMMARY/ABSTRACT Sudden cardiac death (SCD) from ventricular arrhythmias remains the leading cause of death in developed nations, and is rapidly increasing in the rest of the world. The link between efferent sympathetic signaling and SCD has been recognized for a century; however, neuro-modulatory strategies to mitigate SCD have largely been limited. Diversity of neurotransmitters released in the heart, structural and functional remodeling of neurons within the cardiac neuraxis, and alterations in neural information processing are typically not factored in, and remain controversial. Following cardiac injury, widespread structural and neurochemical alterations occur in peripheral ganglia mediating cardiac afferent and efferent neurotransmission, yet, the functional consequences of such changes on intra- and inter-ganglionic signal processing are not understood. In addition, the dynamic nature of the cardiac electrophysiologic substrate is not considered, as changes in efferent sympathetic tone can dramatically alter the cardiac electrophysiologic properties even in scarred hearts. Utilizing multimodal approaches, we will test the hypothesis that the peripheral neural circuitry of SCD can be resolved, and related to cardiac electrophysiological behavior. This idea will be tackled in humans and animal models of ischemic cardiomyopathy and SCD. We will determine molecular, structural, and neurochemical alterations occurring in stellate ganglia, and how they occur. Intra- and inter-ganglionic neural processing by remodeled neurons will be assessed by neuronal recordings using high-throughput, high-density novel arrays, with simultaneous high-density cardiac electrophysiologic mapping. Efferent responses to afferent loads will be examined by detailed mapping of cardiac electrophysiologic and contractile function, and from bioelectric sensors in the myocardial interstitium to determine patterns of classical and non-classical neurotransmitter release. Finally, the arrhythmogenicity of altered processing will be examined in 2D and 3D models of cardiac tissue. If successful, this study will elucidate the neural signature of arrhythmic risk/SCD. The ability to monitor neural signatures and resolve the temporal risk of SCD answers a longstanding question in arrhythmia biology, with significant implications for discovering key therapies that are low cost and be utilized globally.